The modulation of mitochondrial nitric-oxide synthase activity in rat brain development

RIOBO, NATALIA; MELANI, MARIANA; SANJUAN, NORBERTO; FISZMAN, MONICA LIDIA; MARIA CLARA GRAVIELLE; CARRERAS, MARIA CECILIA; CADENAS, ENRIQUE; PODEROSO, JUAN

JOURNAL OF BIOLOGICAL CHEMISTRY

The American Society for Biochemistry and Molecular Biology, Inc.

Año: 2002 vol. 277 p. 42447 - 42455

0021-9258

Different mitochondrial nitric-oxide synthase (mtNOS) isoforms have beendescribed in rat and mouse tissues, such as liver, thymus, skeletal muscle, andmore recently, heart and brain. The modulation of these variants by thyroidstatus, hypoxia, or gene deficiency opens a broad spectrum of mtNOS-dependenttissue-specific functions. In this study, a new NOS variant is described in ratbrain with an M(r) of 144 kDa and mainly localized in the inner mitochondrialmembrane. During rat brain maturation, the expression and activity of mtNOS were maximal at the late embryonic stages and early postnatal days followed by adecreased expression in the adult stage (100 +/- 9 versus 19 +/- 2 pmol of[(3)H]citrulline/min/mg of protein, respectively). This temporal pattern wasopposite to that of the cytosolic 157-kDa nNOS protein. Mitochondrial redoxchanges followed the variations in mtNOS activity: mtNOS-dependent production of hydrogen peroxide was maximal in newborns and decreased markedly in the adultstage, thus reflecting the production and utilization of mitochondrial matrixnitric oxide. Moreover, the activity of brain Mn-superoxide dismutase followed a developmental pattern similar to that of mtNOS. Cerebellar granular cellsisolated from newborn rats and with high mtNOS activity exhibited maximalproliferation rates, which were decreased by modifying the levels of eitherhydrogen peroxide or nitric oxide. Altogether, these findings support the notion that a coordinated modulation of mtNOS and Mn-superoxide dismutase contributes toestablish the rat brain redox status and participate in the normal physiology of brain development.